Phenoxy carboxylic acid derivatives as anti-atherosclerosis agents

ABSTRACT

Anti-atherosclerosis agents having the formula WHEREIN R3, R4 and Y have the same meanings as defined above; and D and E each is hydrogen or halogen are disclosed.   WHEREIN TYPICAL EXAMPLES OF R1 and R2 are hydrogen, C1-C8 alkyl, phenyl, benzyl, and phenethyl, or R1 and R1 may form cycloalkylidene together with a carbon atom bonded therewith; R3 and R4 each is hydrogen or C1-C4 alkyl, Y is hydroxyl, C1-C4 alkoxy, phenoxy or an amine residue, A is hydrogen or a group of the formula,

United States Patent n91 Nakamura et al.

15 i PHENOXY CARBOXYLIC ACID DERIVATIVES AS ANTI-ATHEROSCLEROSIS AGENTS Sumitomo Chemical Company, Ltd., Osaka, Japan [22] Filed: Dec. 10, 1971 [21] Appl. No.: 206,966

Related U.S. Application Data [62] Division of Ser. No. 26,412, April 7, 1970, Pat. No.

[73] Assignee:

[52] U.S. Cl 424/317, 424/308, 424/324 [51] Int. Cl. A6lk 27/00 [58] Field of Search 424/308, 317, 324

[56] References Cited UNITED STATES PATENTS 3,517,051 6/1970 Bolhofer 424/324 3,530,715 12/1971 3,539,628 11/1970 3,652,646 3/1972 3,657,430 4/1972 3,658,967 4/1972 3,679,800 7/1972" 3,681,365 8/1972 Primary Examiner-Albert Meyers [1 1 3,821,404 [451 June 28,- 1974 Assistant ExaminerFrederick E. Waddell Attorney, Agent, or Firm-Stevens, Davis, Miller & Mosher [5 7] ABSTRACT A n1i -a t herosclerosisagenrs having the formula R R R @3320 wherein typical examples of Rand R are hydrogen,

wherein R, R and Y have the same meanings as defined above; and D and E each is hydrogen or halogen I are disclosed.

8 Claims, No Drawings PHENO'XY CARBOXYLIC Acn) DERIVATIVES As ANTI-ATHEROSCLEROSIS AGENTS PI-IENOXY CARBOXYLIC ACID DERIVATIVES This invention relates to novel anti-atherosclerosis agents. More particularly, the invention pertains to novel agents which are useful for the lowering of elevated levels of cholesterol or lipids.

Atherosclerosis is an adult disease for which there is no satisfactory cure. Although the cause of atherosclerosis is not yet known in spite of discussions in the academic circles, it has broadly been recognized that one of the most significant histo-pathological manifestations of atherosclerosis is the deposition of lipids in the blood. Accordingly, research has been directed to the disturbed metabolism of lipids, and attention has been given to the extraordinarily elevated level of cholesterol in the blood.

A number of experimental and clinical facts have been reported, which indicate the relationship between atherosclerosis and elevated blood cholesterol orlipid' level. Hence, the development of agents to reduce the elevated blood cholesterol or lipid level is considered extremely important for the prevention of atheroclero- SIS.

Concentrated efforts have heretofore been made for the development of such agents for lowering cholesterol or lipids and a number of compounds have been tested clinically, but none of them have been proved to be completely satisfactory. Some of them are fairly effective but produce significantly harmful side effects, and others have inadequate effectiveness, so that they are required to be administered in large doses.

The present inventors have found a group of novel compounds which are effective as cholesterol-lowering agents and which are substantially nontoxic.

It is therefore an object of the present invention to provide acholesterolor lipid-lowering agents.

Another object is to provide a process for preparing cholesterolor lipid-lowering agents.

A further object is to provide pharmaceutical compositions containing such agents.

Other objects will be apparent from the following description.

In order to accomplish the above objects, the present invention provides novel phenoxyaliphatic carboxylic acid derivatives of the formula,

wherein R and R represents hydrogen, C -C alkyl, unsubstituted or substituted phenyl, naphthyl, benzyl, or phenethyl, or R and R may form unsubstituted or substituted cycloalkylidene together with a carbon atom bonded therewith; R and R each is hydrogen or C -C alkyl; Y is hydroxyl, C C, alkoxy, phenoxy, or amine residue of the formula,

wherein R and R each is hydrogen, C C, alkyl, unsubstitutedor halogen-, alkylor alkoxy-substituted phenyl, unsubstitutedor halogen-, alkylor alkoxysubstituted aralyl, or unsubstitutedor halogen-, alkylor alkoxy-substituted cycloaklyl; A represents hydrogen or a group of the formula,

wherein G is hydrogen, halogen, C -C alkyl or C -C alkoxy, and p is an integer of 1-5, .and the term unsubstituted or halogen-, alkylor allcoxy-substituted aralkyl meansa group of the formula,

wherein J is lower alkylene, benzylidene or phenethyli: dene, and G and p have the same meanings as defined above, the term unsubstituted or halogen-, alkylor alkoxy-substituted cycloalkyl means a group of the formula, n

wherein G and p have the same meanings asdefined above, and the term unsubstituted or substituted cycloalkylidene formed by R, and R together with a carbon atom bonded therewith means a group of the formula, I

hrm

wherein M is halogen, lower alkyl, phenyl, naphthyl or alkoxy, m is 0 or an integer of 1-5, and n is an integer of 3-8.

Examples of the alkyl of R, R, R R, G and M in clude methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl, and examples of the alkoxy of Y, G and M include methoxy, ethoxy,v n-propoxy, i-propoxy, nbutoxy, i-butoxy and t-butoxy, and examples of the lower alkylene of J include methylene, ethylene, npropylene and i-propylene, and examples of the halogen of D, E, G and M include fluorine, chlorine, bromine and iodine.

These phenoxyaliphatic carboxylic acid derivatives (I) may be prepared by any of the procedures as shown by the following reaction scheme:

PROCEDURE 1 F (JH lz IL -l1 It" in the presence of an alkai R3 R4 R1 -0 oooon PROCEDURE 2 D R3 B4 c X-O-COY R2 OH R3 R4 R1 O OCOY o R! +i PROCEDURE 3 '33 34 R @O CCOOH C -v 11 {Q-o-ru esterificatlon E or amidation 0 Br o E (lb) wherein X is halogen or hydroxyl; A, D, E, R, R R R, and Y have the same meanings as defined above; A ishydrogen or a group of the formula,

wherein R and R have the same meanings as defined above; A" is hydrogen or a group of the formula,

3 R4 CCOY wherein R, R and Y have the same meanings as defined above, and Y is C ,C alkoxy, phenoxy or amine residue of the formula,

wherein R and R have the same meanings as defined above.

The above procedures are illustrated in detail as follows:

Procedure 1 Reaction of a bisphenol derivative (II) with chloroform and a keto-compound (III) in the presence of an alkali In order to carry out the reaction of this procedure, at least 1 mole of chloroform is added drop'wise into a mixture containing -1 mole of a bisphenol derivative (II) and at least 1 mole of a keto-compound (Ill) in the presence of at least 3 moles of an alkali. Examples of the alkali used include sodium hydroxide and potassium hydroxide. The reaction requires a temperature of 20l50C and a reaction time of 3-40 hours. In order to obtain as the main product one of either a phenoxyaliphatic monocarboxylic acid derivative (Ia) (i.e., A H) or a phenoxyaliphatic dicarboxylic acid derivative reaction conditions such as proportions of the reactants, reaction temperature and reaction time should be controlled carefully. In the case where about 1 mole of the ketocompound (III), about 1 mole of chloroform and/or about 3 moles of the alkali are used per 1 mole of the bisphenol derivative (II), a phenoxy aliphatic monocarboxylic acid derivative (la) (i.e., A: H) is obtained as the main product. On the other hand, when all the keto-compound, chloroform and the alkali are used in an excessive amount, a bisphenoxyaliphatic dicarboxylic acid derivative (Ia),

is obtained as the main product.

When a phenoxyaliphatic monocarboxylic acid derivative (Ia) (i.e., A H) and a phenoxyaliphatic dicarboxylic acid derivative (Ia) (i.e.,

a 4 ie swqal are produced at the same time, they can be separated from each other by an ordinary purification method r such as recrystallization or chromatography.

The reaction may be carried out in the presence of excess chloroform and/or the keto-compound (III) or in the presence or absence of an inert reaction medium. Examples of the reaction medium include dioxane, benzene, toluene, etc.

Bisphenol derivatives of the formula (II) employed as starting material can be obtained by a method disclosed, for example, in J.A.C.S., 61, 345 (I939).

Procedure 2 Condensation reaction of a bisphenol derivative (II) with an a-halogenoor hydroxy-aliphatic carboxylic acid derivative (IV) In case X is halogen, 1 mole of a bisphenol derivative (II) is dissolved or suspended in an inert reaction medium and contacted with at least 1 mole of an alkaline agent to form an alkaline salt, and then at least 1 mole of an a-halogenated aliphatic acid derivative (IV) (i.e.,

x halogen) is added into the resultant reaction mixture to start the condensation reaction. After the reaction is over, the reaction mixture is treated according reaction conditions such as proportions of the reactants, reaction temperature and reaction time should be controlled carefully. If the alkaline agent and/or the a-halogeno-aliphatic acid derivative (IV) are used in an equimolar amount of the bisphenol derivative (II), a phenoxy-aliphatic monocarboxylic acid derivative (I) (i.e., A H) is mainly obtained. On the other hand, if

both the alkaline agent and the a-halogeno-aliphatic acid derivative (IV) are used in an amount not less than 2 moles per mole of the bisphenol derivative (II), a phenoxyaliphatic dicarboxylic acid derivative (I) In case X is a hydroxyl group, 1 mole of a bisphenol derivative (II) is contacted with at least 1 moleof an a-hydroxyaliphatic acid derivative (IV) (i.e., X OH) in the presence of an acidic catalyst such as sulfuric acid, p-toluene-sulfonyl chloride, arsenic acid. boric acid, sodium hydrogensulate, potassium hydrogensulfate, etc. in the presence or absence of an inert reaction medium. Examples of the reaction medium used 6i include benzene, toluene, dioxane, etc. The acid catalyst is used in an amount of 0.010.5 mole per 1 mole of a bisphenol derivative. The reaction requires a temperature of IO9OC.

v In order to obtain mainly one of either a phenoxyaliphatic monocarboxylic acid derivative (I) (ie A H) or a phenoxy-aliphatic dicarboxylic acid derivative as described above, reaction conditions such as proportions of the reactants, reaction temperature and reaction time should be controlled carefully.

Procedure 3 Esterification or amidation of a phenoxyaliphatic acid derivative (la) A phenoxyaliphatic carboxylic acid derivative (la) or its reactive ester is converted into an ester or amide (lb) by ordinary esterification or amidation procedures, for example by treatment with an esterifying agent or an amine compound or ammonia. In this process, the term reactive ester of the phenoxyaliphatic carboxylic acid derivative (la) means an acyl halide, an intramolecular acid anhydride, an ester of the acid, a salt of the acid, etc. and the term esterification agent" means an alcohol, phenol, diazomethane, a dialkyl sulfate, an alkyl halide, an alkylhalogenosulfite, etc.

Esterification (or amidation) of a phenoxyaliphatic monocarboxylic acid derivative '(la) (i.e., A hydrogen) gives only a monester (or a monoamide) derivative (lb) (i.e., A" F hydrogen atom), however, esterification (or amidation) of a phenoxyaliphatic dicarboxylic acid derivative (la) R3 R4 i-srsE-QQQQ give a diester (or a diamide) derivative (lb) a R4: i-sstiis99212- and a monoester (or a monoamide) derivative (lb) (i.e., A" =-I-l) depending upon the reactionconditions such as proportions of the reactants, reaction temperature and reaction time.

For example, a diester (lb) and Y 'alkoxy) is obtained by reacting lmole of a phenoxyaliphatic dicarboxylic acid derivative loam) with at least 2 moles of an alcohol or at least 2 moles of diazomethane, or. by reacting 1 mole of a salt of the phenoxyaliphatic dicarboxylic acid derivative with at least 2 moles of a dialkyl sulfate, an alkylhalide or an alkyl halogenosulfite, or by reacting l mole of an acid halide or an intramolecular acid anhydride of the phenoxyaliphatic dicarboxylic acid derivative with at least 7 2 moles of an alcohol or phenol. The reaction of the intramolecular acid anhydride of the phenoxyaliphatic dicarboxylic acid derivative with the alcohol or phenol may give also a monoester (lb), (i.e., A H and Y alkoxy or phenoxy).

The phenoxyaliphatic carboxylic acid derivative (la used as a starting material of this procedure is obtained by the above-mentioned procedure 1 or procedure 2.

In the present invention, the phenoxyaliphatic carboxylic acid derivative (1) wherein Y is hydroxyl and/or A is hydrogen can be converted to a salt by treatment with an alkali. The salt is formed at the carboxyl and/or phenolic hydroxyl. An alkali metal salt can be obtained by contacting the phenoxyaliphatic carboxylic acid derivative (I) wherein Y is hydroxyl and/or A is hydrogen with sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or ammonia, etc., or with an alcoholate or an alkali metal such as sodium methylate in an organic solvent, preferably in a lower alkanol such as methanol or ethanol, or with hydroxide, carbonate or bicarbonate of an alkali metal in an organic solvent, preferably in acetone or methanol, if necessary in the presence of a small amount of water. The alkali metal salt thus obtained can be converted to an alkaline earth metal salt by treatment with a salt of an alkaline earth metal such as calcium chloride.

According to the present invention, the following phenoxyaliphatic carboxylic acid derivativesare obtained.

There can also be prepared methyl esters, ethyl esters, n-propyl esters, iso-propyl esters, n-butyl esters, iso-butyl esters or t-butyl esters of the abovementioned monocarboxylic acids and sodium, potassium, calcium, magnesium, aluminum or ammonium salts of the above-mentioned monocarboxylic acids.

In the above exemplified compounds, B means a group of the formula and B means a group of the formula The present invention further provides a pharmaceutical composition containing a phenoxyaliphatic carboxylic acid derivative of the formula,

C 112/ Zip wherein R R each is hydrogen, C -C alkyl, unsubstitutedor halogen-, alkylor alkoxy-substituted phenyl, unsubstitutedor halogen-, alkylor alkoxysubstituted aralyl, or unsubstituted or halogen-, alkylor alkoxy-substituted cycloalkyl; A represents hydrogen or a group of the formula,

. R 0 0 OY wherein R R and Y have the same meanings as defined above; and D and E each is hydrogen or halogen. The cholesterol-lowering agents of this invention may be, for example, orally administered. Usually the amount orally administered is 0.01 g. --l0 g. per day/- human adult, preferably 0.05 g. 3 g. per day/human adult. The cholesterol-lowering agent may be in any suitable form which is conventional for oral administration. Thus, it may be encased in a capsule, or it may be in a liquid form, in a tablet form, or in a powder form. In preparing the agents in these various forms, the active compound may be mixed with or impregnated in a suitable solid carrier.

The process of the present invention is illustrated in more detail by the following examples, however it is not intended to limit the invention.

EXAMPLES 1 18 General Procedure Into a mixture of a bishydroxyphenyl derivative and a ketone compound was added crushed potassium hydroxide or sodium hydroxide. Chloroform was added dropwise into the above mixture with stirring at 20 C, and the resultant mixture was heated at 50 C to complete the reaction. Thereafter the reaction mixture was concentrated to give a residue. Into the residue was added water. After cooling, the resultant mixture was treated with activated charcoal and acidified by diluted hydrochloric acid or sulfuric acid to give an oily substance. The oily substance was extracted by ether and the ether solution was contacted with aqueous diluted Na CO solution. The separated aqueous layer was washed with ether, acidified and again extracted with ether. The obtained ether layer was dried over anhydrous sodium sulfate and concentrated to give a crude product which was purified by recystallization or chromatography.

Results are summarized in Table l.

EXAMPLES l9 29 General Procedure into a mixture consisting of a bis-(4-hydroxy-phenyl) derivative and dry toluene was added a toluene suspension of sodium hydride under cooling. After stirring the mixture for a short time, a mixture of an a-halogeno aliphatic acid derivative and toluene was added dropwise thereto, and heated with stirring for several hours. After cooling, the reaction mixture was washed with water. The toluene was distilled off to yield a crude produce which was purified by recrystallization or column chromatography.

Results are summarized in Table 2.

EXAMPLES 30 31 General Procedure Into a mixture containing a bis-(4-hydroxyphenyl) derivative and ethyl a-hydroxy-isobutyrate was added 10 20 percent sulfuric acid at 20-80C. After the completion of the addition of sulfuric acid, the reaction mixture was stirred at the same temperature." After cooling, the reaction mixture was washed with water, and was treated with diluted sodium carbonate and benzene. Then the crude product obtained was purified by recrystallization of column chromatography or other suitable purification method.

Results are summarized in Table 3.

EXAMPLES 32 47 General Procedure A mixture consisting of a phenoxyaliphatic acid derivative, an alcohol, a few drops of concentrated sulfuric acid and, if necessary, benzene was refluxed for a determined period of time, while removing produced water together with a solvent- The solvent was added to the reaction mixture to keep a constant amount. After the reaction was over, the mixture was washed with water, dried over anhydrous sodium sulfate and concentrated to yield a crude product, which was purified by recrystallization or column chromatography.

The results are summarized in Table 4.

EXAMPLES 48 51 General Procedure EXAMPLE 52 Into a mixture of 28 percent aqueous ammonia (10 ml.) and 1,2-dichloroe'thane (50 ml.) was added dropwise a mixture of 1,2-dichlorethane (30 ml.) and an acid chloride (9 g) which was obtained by reacting 10 g of 1,1 bis(4'-hydroxyphenyl) cyclohexane-0,0- diisobutyric acid and 5 g of thionyl chloride. The temperature of the reaction mixture was kept at 0-5C during the addition. After the completion of the addition, the reaction mixture was stirred at C for 5 hours, washed with water and dried. The solvent was distilled off to give a pale yellow crystal (4 g) of the desired product, which was purified by recrystallization.

Elementary analysis C (71) H (71) N (9:) Cal. 71.20 7.82 6.39 Found 70.92 7.76 6.37

TABLE 1 Starting materials Found Elementary analysis (percent) Calcd.

Product Physical property Reaction KOH or N aOH R C0B (g.) (temp) (temp) Chemical structure (g.) 24 g.

M.P. 159160 C. O C(CHa)zCO OH] (from benzene) 2 CHaCOCHa, 61 g- KOH, 17 OH] g. 

2. The method of claim 1, wherein said phenoxyaliphatic carboxylic acid derivative is of the formula,
 3. The method of claim 1, wherein said phenoxyaliphatic carboxylic acid derivative is of the formula,
 4. The method of claim 1, wherein said phenoxyaliphatic carboxylic acid derivative is of the formula,
 5. A pharmaceutical composition consisting of an elevated cholesterol or lipid level lowering effective amount of a phenoxyaliphatic carboxylic acid derivative of the formula,
 6. The pharmaceutical composition of claim 5, wherein said phenoxyaliphatic carboxylic acid derivative is of the formula,
 7. The pharmaceutical composition of claim 5, wherein said phenoxyaliphatic carboxylic acid derivative is of the formula,
 8. The pharmaceutical composition of claim 5, wherein said phenoxyaliphatic carboxylic acid derivative is of the formula, 